Scaffold-free generation of uniform adipose spheroids for metabolism research and drug discovery

Klingelhutz, Aloysius J.; Gourronc, Françoise A.; Chaly, Anna L; Wadkins, David; Burand, Anthony J.; Markan, Kathleen R.; Idiga, Sharon O.; Wu, Meng; Potthoff, Matthew J.; Ankrum, James A.

doi:10.1038/s41598-017-19024-z

Cited by 110 publications

(137 citation statements)

References 52 publications

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“…In addition, Yang et al reported that murine adipose derived stromal cells were successfully differentiated into mature adipocytes with BAT pheno-type and function within 3D hydrogels [50]. For WA, 3D culture has been demonstrated to promote adipogenesis and adipokine secretion compared to 2D culture [51,52]. It has also been demonstrated that a porous structure could improve the cell viability in vitro and promote cell ingrowth and integration in vivo [35,53].…”

Section: Discussionmentioning

confidence: 99%

Effects of tunable, 3D-bioprinted hydrogels on human brown adipocyte behavior and metabolic function

Kuss

Kim

et al. 2018

Acta Biomaterialia

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Obesity and its related health complications cause billions of dollars in healthcare costs annually in the United States, and there are yet to be safe and long-lasting anti-obesity approaches. Using brown adipose tissue (BAT) is a promising approach, as it uses fats for energy expenditure. However, the effect of the microenvironment on human thermogenic brown adipogenesis and how to generate clinically relevant sized and functioning BAT are still unknown. In our current study, we evaluated the effects of endothelial growth medium exposure on brown adipogenesis of human brown adipose progenitors (BAP). We found that pre-exposing BAP to angiogenic factors promoted brown adipogenic differentiation and metabolic activity. We further 3D bioprinted brown and white adipose progenitors within hydrogel-based bioink with controllable physicochemical properties and evaluated the cell responses in 3D bioprinted environments. We used soft, stiff, and stiff-porous constructs to encapsulate the cells. All three types had high cell viability and allowed for varying levels of function for both white and brown adipocytes. We found that the soft hydrogel constructs promoted white adipogenesis, while the stiff-porous hydrogel constructs improved both white and brown adipogenesis and were the optimal condition for promoting brown adipogenesis. Consistently, stiff-porous hydrogel constructs showed higher metabolic activities than stiff hydrogel constructs, as assessed by 2-deoxy glucose uptake (2-DOG) and oxygen consumption rate (OCR). These findings show that the physicochemical environments affect the brown adipogenesis and metabolic function, and further tuning will be able to optimize their functions. Our results also demonstrate that 3D bioprinting of brown adipose tissues with clinically relevant size and metabolic activity has the potential to be a viable option in the treatment of obesity and type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Effects of tunable, 3D-bioprinted hydrogels on human brown adipocyte behavior and metabolic function

Kuss

Kim

et al. 2018

Acta Biomaterialia

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“…Differentiation of these cultures allowed lipid accumulation and these cultures secreted leptin, the archetypal adipokine. Other groups used adipose progenitors derived from the stromal-vascular fraction of human white adipose tissue and self-organised them into spheroids in hanging drops [81] or by first stirring and then embedding them in Matrigel they generated self-organised vascularised organoids [82]. These novel protocols open the door to using long-term patient-derived adipose cultures to explore the pathology of adipose tissue in metabolic disease.…”

Section: Don't Believe the Hype: Organoid Limitationsmentioning

confidence: 99%

Diabetes through a 3D lens: organoid models

2020

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Diabetes is one of the most challenging health concerns facing society. Available drugs treat the symptoms but there is no cure. This presents an urgent need to better understand human diabetes in order to develop improved treatments or target remission. New disease models need to be developed that more accurately describe the pathology of diabetes. Organoid technology provides an opportunity to fill this knowledge gap. Organoids are 3D structures, established from pluripotent stem cells or adult stem/progenitor cells, that recapitulate key aspects of the in vivo tissues they mimic. In this review we briefly introduce organoids and their benefits; we focus on organoids generated from tissues important for glucose homeostasis and tissues associated with diabetic complications. We hope this review serves as a touchstone to demonstrate how organoid technology extends the research toolbox and can deliver a step change of discovery in the field of diabetes.

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“…Adipose : Due to its central metabolic role in the regulation of energy homeostasis, adipose tissue is gaining more and more interest as an in vitro model in the context of metabolic disorders . Spheroid models, capable of accumulating and releasing fatty acids, have been formed with established cell lines and primary adipose‐derived stem cells …”

Section: Transferable In Vitro Organ Modelsmentioning

confidence: 99%

Integrated Microphysiological Systems: Transferable Organ Models and Recirculating Flow

et al. 2019

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Advanced 3D in vitro models (organoids or tissue cultures) may constitute an alternative test system for initial screening and characterization of lead compounds in early development stages. 3D tissue structures have been proven to more closely reproduce behavior and characteristics of a living organism in comparison to traditional 2D cell cultures in dishes. [3,4] For such advanced in vitro models, a large range of automated test systems and analysis methods would be potentially available, so that testing procedures could be parallelized to increase throughput. This prospect has fueled rapid progress in developing 3D in vitro models of individual organs of the human body for pharmaceutical and toxicological research. Such model systems need to be carefully engineered to faithfully reproduce physiological effects, pharmacokinetics, and toxicity that may occur within a human body in order to enable successful identification of new drug compounds and the corresponding mechanisms of action.To realize advanced in vitro models, not only the 3D nature of a human body and its tissues needs to be considered, but also the potential interplay of organs. More recently, microphysiological systems (MPSs) emerged in an effort to better recapitulate in vivo conditions of human physiology and to better control in vitro cell and tissue culturing conditions. [5][6][7][8][9][10] MPSs are in vitro platforms designed to model the spatial, chemical, structural, and physiological elements of in vivo cellular environments and include, in most cases, a combination of advanced cell-culture or tissue models and microfluidic technology. Important features of MPSs include the use of more complex multicellular or tissue structures and the possibility to expose cells to cues that they also experience in their native environment in the human body, such as mechanical cues in the form of flow-induced shear stress, [11,12] stretching, [13,14] or biochemical stimuli. [15][16][17] Key features of MPSs that are usually combined in a single system include: a) advanced 3D tissue or organ models, b) the presence of culture medium flow or perfusion, and c) fluidic interconnection and potential interaction of different organ models through the liquid phase: a) 3D tissue models feature increased functionality and a more organotypic cellular microenvironment in comparison to Studying and understanding of tissue and disease mechanisms largely depend on the availability of suitable and representative biological model systems. These model systems should be carefully engineered and faithfully reproduce the biological system of interest to understand physiological effects, pharmacokinetics, and toxicity to better identify new drug compounds. By relying on microfluidics, microphysiological systems (MPSs) enable the precise control of culturing conditions and connections of advanced in vitro 3D organ models that better reproduce in vivo environments. This review focuses on transferable in vitro organ models and integrated MPSs that host these transferable biologic...

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Scaffold-free generation of uniform adipose spheroids for metabolism research and drug discovery

Cited by 110 publications

References 52 publications

Effects of tunable, 3D-bioprinted hydrogels on human brown adipocyte behavior and metabolic function

Effects of tunable, 3D-bioprinted hydrogels on human brown adipocyte behavior and metabolic function

Diabetes through a 3D lens: organoid models

Integrated Microphysiological Systems: Transferable Organ Models and Recirculating Flow

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